Concordance of CSF biomarkers with amyloid PET at baseline in EMERGE/ENGAGE, phase 3 studies of aducanumab in patients with early Alzheimer’s disease

Abstract

AbstractBackgroundRecent technical performance improvements with the introduction of fully automated platforms have made cerebrospinal fluid (CSF) biomarkers attractive alternatives to positron emission tomography (PET) for brain amyloid pathology confirmation in the diagnosis of Alzheimer’s disease. Growing the body of evidence demonstrating high agreement between CSF biomarkers and amyloid PET across multiple automated platforms is critical to ensuring widespread access to and adoption of CSF biomarkers. Adding to previous data generated with Lumipulse® CSF immunoassays, this study assessed CSF biomarkers on the Elecsys® platform as valid alternatives to PET for amyloid confirmation by conducting a concordance analysis using data from EMERGE and ENGAGE, including performance evaluation of the Elecsys® Gen2 recommended cutoff.MethodsEMERGE and ENGAGE were randomized, double‐blind, placebo‐controlled, global Phase 3 studies of aducanumab. Participants were 50‐85 years old and met clinical criteria for mild cognitive impairment due to AD or mild AD dementia. All enrolled participants had amyloid pathology detected by amyloid PET (visual read) during screening. Positive percent agreement (sensitivity), negative percent agreement (specificity), and overall percent agreement (OPA) were determined (with amyloid PET visual read as reference standard) for the following CSF biomarkers (and applicable ratios) using the Elecsys® immunoassay: using an internal cutoff value maximizing the Youden J index for Abeta40, Abeta42, phosphorylated tau (ptau181), tau; Abeta40/Abeta42, ptau181/Abeta42, tau/Abeta42; and for the ptau181/Abeta42 ratio using the Elecsys® Gen2 cutoff.ResultsN=349 participants (n=309 PET positive; n=40 PET negative) provided CSF at screening and were included in the analysis. Using internal cutoff values, tau, ptau181 and Abeta42 demonstrated OPA of 69%, 83% and 89% respectively, and CSF biomarker ratios showed increased diagnostic accuracy (OPA ≥95% for all ratios assessed). The Elecsys® Gen2 cutoff demonstrated excellent sensitivity(93%), specificity(82%), and OPA(92%).ConclusionsThese analyses demonstrate robust concordance between CSF biomarkers and amyloid PET visual read in EMERGE/ENGAGE and align with results generated previously. This supports the interchangeability of these biomarker methods for determination of amyloid positivity and applicability of the Elecsys® recommended cutoff in similar patient populations, with significant potential to improve accessibility of this critical biomarker for AD diagnosis in clinical trials and clinical practice.